Lipid raft disruption inhibits the activation of Transient Receptor Potential Vanilloid 1, but not TRP Melastatin 3 and the voltage-gated L-type calcium channels in sensory neurons.

Transient Receptor Potential (TRP) ion channels like Vanilloid 1 (TRPV1) and Melastatin 3 (TRPM3) are nonselective cation channels expressed in primary sensory neurons and peripheral nerve endings, which are located in cholesterol- and sphingolipid-rich membrane lipid raft regions and have important roles in pain processing. Besides TRP ion channels a wide variety of voltage-gated ion channels were also described in the membrane raft regions of neuronal cells. Here we investigated the effects of lipid raft disruption by methyl-beta-cyclodextrin (MCD) and sphingomyelinase (SMase) on TRPV1, TRPM3 and voltage-gated L-type Ca channel activation in cultured trigeminal neurons and sensory nerve terminals of the trachea.

Novel Piperazine Derivatives of Vindoline as Anticancer Agents.

A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 -substituted piperazine pharmacophores at positions 10 and 17 of alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects.

Osteosarcoma-Induced Pain Is Mediated by Glial Cell Activation in the Spinal Dorsal Horn, but Not Capsaicin-Sensitive Nociceptive Neurons: A Complex Functional and Morphological Characterization in Mice.

Bone cancer and its related chronic pain are huge clinical problems since the available drugs are often ineffective or cannot be used long term due to a broad range of side effects. The mechanisms, mediators and targets need to be identified to determine potential novel therapies. Here, we characterize a mouse bone cancer model induced by intratibial injection of K7M2 osteosarcoma cells using an integrative approach and investigate the role of capsaicin-sensitive peptidergic sensory nerves.

Anti-Nociceptive Effects of Sphingomyelinase and Methyl-Beta-Cyclodextrin in the Icilin-Induced Mouse Pain Model.

The thermo- and pain-sensitive Transient Receptor Potential Melastatin 3 and 8 (TRPM3 and TRPM8) ion channels are functionally associated in the lipid rafts of the plasma membrane. We have already described that cholesterol and sphingomyelin depletion, or inhibition of sphingolipid biosynthesis decreased the TRPM8 but not the TRPM3 channel opening on cultured sensory neurons. We aimed to test the effects of lipid raft disruptors on channel activation on TRPM3- and TRPM8-expressing HEK293T cells in vitro, as well as their potential analgesic actions in TRPM3 and TRPM8 channel activation involving acute pain models in mice.

Transient Receptor Potential Ankyrin 1 Ion Channel Is Expressed in Osteosarcoma and Its Activation Reduces Viability.

Osteosarcoma is a highly malignant, painful cancer with poor treatment opportunities and a bad prognosis. Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are non-selective cation channels that have been of great interest in cancer, as their expression is increased in some malignancies. In our study we aim to characterize the expression and functionality of the TRPA1 and TRPV1 channels in human and mouse osteosarcoma tissues and in a mouse cell line.

Cyclodextrin derivatives decrease Transient Receptor Potential vanilloid 1 and Ankyrin 1 ion channel activation via altering the surrounding membrane microenvironment by cholesterol depletion.

Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are nonselective cation channels expressed in primary sensory neurons and several other non-neuronal structures such as immune cells, keratinocytes, and vascular smooth muscle cells. They play important roles in nociception, pain processing and their chanellopathies are associated with the development of several pathological conditions. They are located in cholesterol- and sphingolipid-rich membrane lipid raft regions serving as platforms to modulate their activations.

Lipid raft disruption as an opportunity for peripheral analgesia.

Chronic pain conditions are unmet medical needs, since the available drugs, opioids, non-steroidal anti-inflammatory/analgesic drugs and adjuvant analgesics do not provide satisfactory therapeutic effect in a great proportion of patients. Therefore, there is an urgent need to find novel targets and novel therapeutic approaches that differ from classical pharmacological receptor antagonism. Most ion channels and receptors involved in pain sensation and processing such as Transient Receptor Potential ion channels, opioid receptors, P2X purinoreceptors and neurokinin 1 receptor are located in the lipid raft regions of the plasma membrane.

The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi.

This paper is dedicated to the memory of János Szolcsányi (1938-2018), an outstanding Hungarian scientist. Among analgesics that act on pain receptors, he identified capsaicin as a selective lead molecule. He studied the application of capsaicin and revealed several physiological (pain, thermoregulation) and pathophysiological (inflammation, gastric ulcer) mechanisms.

Hemokinin-1 induces transcriptomic alterations in pain-related signaling processes in rat primary sensory neurons independent of NK1 tachykinin receptor activation.

The tachykinin hemokinin-1 (HK-1) is involved in immunological processes, inflammation, and pain. Although the neurokinin 1 receptor (NK1R) is described as its main target, several effects are mediated by currently unidentified receptor(s). The role of HK-1 in pain is controversial, depending on the involvement of peripheral and central sensitization mechanisms in different models.

Molecular Links between Sensory Nerves, Inflammation, and Pain 2.0.

Capsaicin-sensitive peptidergic sensory nerves mediate triple actions: besides transmitting sensory and pain signals to the central nervous system (afferent function), they also have local and systemic efferent functions [...

Elucidation of the binding mode of organic polysulfides on the human TRPA1 receptor.

Previous studies have established that endogenous inorganic polysulfides have significant biological actions activating the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor. Organic polysulfides exert similar effects, but they are much more stable molecules, therefore these compounds are more suitable as drugs. In this study, we aimed to better understand the mechanism of action of organic polysulfides by identification of their binding site on the TRPA1 receptor.

The heptapeptide somatostatin analogue TT-232 exerts analgesic and anti-inflammatory actions via SST receptor activation: In silico, in vitro and in vivo evidence in mice.

Since the conventional and adjuvant analgesics have limited effectiveness frequently accompanied by serious side effects, development of novel, potent pain killers for chronic neuropathic and inflammatory pain conditions is a big challenge. Somatostatin (SS) regulates endocrine, vascular, immune and neuronal functions, cell proliferation through 5 G protein-coupled receptors (SST-SST). SS released from the capsaicin-sensitive peptidergic sensory nerves mediates anti-inflammatory and antinociceptive effects without endocrine actions via SST.

Effect of Lipid Raft Disruptors on Cell Membrane Fluidity Studied by Fluorescence Spectroscopy.

Lipid rafts are specialized microdomains in cell membranes, rich in cholesterol and sphingolipids, and play an integrative role in several physiological and pathophysiological processes. The integrity of rafts can be disrupted via their cholesterol content-with methyl-β-cyclodextrin (MCD) or with our own carboxamido-steroid compound (C1)-or via their sphingolipid content-with sphingomyelinase (SMase) or with myriocin (Myr). We previously proved by the fluorescent spectroscopy method with LAURDAN that treatment with lipid raft disruptors led to a change in cell membrane polarity.

PACAP-38 Induces Transcriptomic Changes in Rat Trigeminal Ganglion Cells Related to Neuroinflammation and Altered Mitochondrial Function Presumably via PAC1/VPAC2 Receptor-Independent Mechanism.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a broadly expressed neuropeptide which has diverse effects in both the peripheral and central nervous systems. While its neuroprotective effects have been shown in a variety of disease models, both animal and human data support the role of PACAP in migraine generation. Both PACAP and its truncated derivative PACAP(6-38) increased calcium influx in rat trigeminal ganglia (TG) primary sensory neurons in most experimental settings.

Synthetic Diphenylacetylene-Based Retinoids Induce DNA Damage in Chinese Hamster Ovary Cells without Altering Viability.

All-trans-retinoic acid (ATRA), the active metabolite of vitamin A, plays a pivotal role in cell differentiation, proliferation and embryonic development. It is an effective therapy for dermatological disorders and malignancies. ATRA is prone to isomerization and oxidation, which can affect its activity and selectivity.

Functional Transient Receptor Potential Ankyrin 1 and Vanilloid 1 Ion Channels Are Overexpressed in Human Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a common cancer with poor prognosis. Transient Receptor Potential Ankyrin 1 (TRPA1) and Vanilloid 1 (TRPV1) receptors are non-selective cation channels expressed on primary sensory neurons and epithelial and immune cells. TRPV1 mRNA and immunopositivity, as well as TRPA1-like immunoreactivity upregulation, were demonstrated in OSCC, but selectivity problems with the antibodies still raise questions and their functional relevance is unclear.

Desensitization of Capsaicin-Sensitive Afferents Accelerates Early Tumor Growth Increased Vascular Leakage in a Murine Model of Triple Negative Breast Cancer.

There is growing interest in the role of nerve-driven mechanisms in tumorigenesis and tumor growth. Capsaicin-sensitive afferents have been previously shown to possess antitumoral and immune-regulatory properties, the mechanism of which is currently poorly understood. In this study, we have assessed the role of these terminals in the triple negative 4T1 orthotopic mouse model of breast cancer.

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.

SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy.

, and Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST Receptor Agonists.

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST) without influencing endocrine functions. Therefore, SST is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need. Here, we examined the binding, SST-linked G protein activation and β-arrestin activation on stable SST expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.

Qualitative and Quantitative Phytochemical Analysis of Hairy Root Cultures.

Hairy root cultures are genetically and biochemically stable, and they regularly possess the same or better biosynthetic capabilities for specialized (secondary) metabolite production compared to the intact plant. species are well-known herbal remedies in ethnopharmacology and rich sources of isoflavonoids. Besides isoflavones, less prevalent isoflavones and pterocarpans with valuable biological effects can be found in species as well.

Analgesic Effects of Lipid Raft Disruption by Sphingomyelinase and Myriocin via Transient Receptor Potential Vanilloid 1 and Transient Receptor Potential Ankyrin 1 Ion Channel Modulation.

Transient Receptor Potential (TRP) Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons, and integratively regulate nociceptor and inflammatory functions. Lipid rafts are liquid-ordered plasma membrane microdomains rich in cholesterol, sphingomyelin and gangliosides. We earlier showed that lipid raft disruption inhibits TRPV1 and TRPA1 functions in primary sensory neuronal cultures.

Hemokinin-1 as a Mediator of -Related Pain via Direct Activation of Primary Sensory Neurons.

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain.

Analyzing the Carotenoid Composition of Melilot ( (L.) Pall.) Extracts and the Effects of Isolated (All-)-lutein-5,6-epoxide on Primary Sensory Neurons and Macrophages.

is known to contain several types of secondary metabolites. In contrast, the carotenoid composition of this medicinal plant has not been investigated, although it may also contribute to the biological activities of the drug, such as anti-inflammatory effects. Therefore, this study focuses on the isolation and identification of carotenoids from Meliloti herba and on the effect of isolated (all-)-lutein 5,6-epoxide on primary sensory neurons and macrophages involved in nociception, as well as neurogenic and non-neurogenic inflammatory processes.